Abstract

Alcohol and substance use disorders (SUDs) are common, moderately heritable, and associated with substantial burden of disease. Improving prevention strategies requires elucidating whether SUD correlates may represent risk factors for and/or consequences of substance use initiation and progression. The two studies presented here use genetically informed developmental samples to: 1) characterize associations between SUD genetic risk and a wide range of potentially relevant phenotypes measured in childhood, largely prior to the onset of substance use, 2) test whether internalizing and externalizing psychiatric symptoms and indices of executive function precede and/or follow alcohol use transitions (e.g., initiation, problematic use), and 3) test whether polygenic liability to these phenotypes are associated with onset of symptoms and/or transitions in alcohol use. Study 1, a Phenome-wide Association Study (PheWAS) of SUD polygenic risk using data from the Adolescent Brain Cognitive Development (ABCD) Study (n=1,548 individuals genetically similar to African reference populations, n=5,556 individuals genetically similar to European reference populations; ages 8-13), yielded insights into the phenotypic spectrum of associations with SUD genetic risk across mental health, screen time, and other psychosocial domains and potential neural mechanisms underlying these associations, including among substance-naive individuals. Results from Study 2 (Collaborative Study on the Genetics of Alcoholism [COGA] prospective study, n=3,681, ages 11-36) generally showed that externalizing symptoms were prospectively associated with risk for alcohol use and problems, and social anxiety with progression to severe AUD, and that initiation and AUD were linked with the development of depression, suicidal ideation, and conduct disorder symptoms. Polygenic risk for problematic alcohol use was linked to suicidal ideation; no other polygenic risk associations were identified. Through agnostic and hypothesis-driven polygenic score and longitudinal analyses, these two studies emphasize the putatively predispositional role of externalizing behaviors in alcohol use and SUD risk, the specificity of internalizing problems to later and/or more problematic use, and additional phenotypes, such as screen time, caffeine and sugary beverage consumption that may represent phenotypic expression of SUD risk prior to the onset of substance use. Additional work is needed to interrogate potential causal mechanisms linking predispositional risk to substance involvement, psychiatric symptoms, and correlated phenotypes.

Committee Chair

Ryan Bogdan

Committee Members

Alex Miller; Deanna Barch; Joshua Jackson; Kathleen Bucholz

Degree

Doctor of Philosophy (PhD)

Author's Department

Psychology

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

6-4-2026

Language

English (en)

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Available for download on Friday, May 28, 2027

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